Cognitive impact of neuronal antibodies: encephalitis and beyond

Abstract

Cognitive dysfunction is a common feature of autoimmune encephalitis. Pathogenic neuronal surface antibodies are thought to mediate distinct profiles of cognitive impairment in both the acute and chronic phases of encephalitis. In this review, we describe the cognitive impairment associated with each antibody-mediated syndrome and, using evidence from imaging and animal studies, examine how the nature of the impairment relates to the underlying neuroimmunological and receptor-based mechanisms. Neuronal surface antibodies, particularly serum NMDA receptor antibodies, are also found outside of encephalitis although the clinical significance of this has yet to be fully determined. We discuss evidence highlighting their prevalence, and association with cognitive outcomes, in a number of common disorders including cancer and schizophrenia. We consider mechanisms, including blood-brain barrier dysfunction, which could determine the impact of these antibodies outside encephalitis and account for much of the clinical heterogeneity observed.

Fig. 1. NMDAR encephalitis.

a NMDAR-antibody access to the brain; b Molecular mechanisms of pathogenicity; c Functional effects of the NMDAR-antibodies; d Functional connectivity changes in NMDAR encephalitis. (Left) Impaired functional connectivity between the hippocampus and the medial prefrontal cortex identified using independent component analysis and dual regression. The severity of hippocampal functional connectivity impairment correlates with individual memory deficits. (Middle) Impaired connectivity of the hippocampus with the medial prefrontal cortex replicated using a seed-based approach. In addition, reduced hippocampal connectivity with other regions of the default mode network was observed, e.g. the posterior cingulate cortex and the precuneus. (Right) Using a network-based approach, significantly reduced functional connectivity was found within several large-scale networks, including the medial temporal lobe network, the sensorimotor network and the visual network. [Figures reproduced with permission from^,] e Clinical phenotype. LGI1 encephalitis: a Molecular mechanisms of pathogenicity; b Functional effects of the LGI1-antibodies; c Patients with LGI1 encephalitis had increased functional connectivity of the dorsal and ventral default mode network (DMN) that correlated with working memory (dorsal DMN) and episodic memory (ventral DMN) performance. [Figures reproduced with permission from]; d Clinical phenotype. CASPR2 encephalitis and Morvan’s Syndrome: a Molecular mechanisms of pathogenicity; b Functional effects of the CASPR2-antibodies; c Bilateral FLAIR hyperintense signal and mild atrophy of the hippocampus in a patient with CASPR2 encephalitis; d Clinical phenotype. Components of this figure were created using Servier Medical Art templates, which are licensed under a Creative Commons Attribution 3.0 Unported License; https://smart.servier.com. The shapes of the electrophysiological traces were modelled on data published in^,,.